INTERVENTIONAL CARDIOLOGY Cardiology Journal 20XX, Vol. XX, No. X, XXX–XXX DOI: 10.5603/CJ.a2020.0164 Copyright © 20XX Via Medica REVIEW ARTICLE ISSN 1897–5593 eISSN 1898–018X Antiplatelet effects of prostacyclin analogues: Which one to choose in case of thrombosis or bleeding? Sylwester P. Rogula1*, Hubert M. Mutwil1*, Aleksandra Gąsecka1, Marcin Kurzyna2, Krzysztof J. Filipiak1 11st Chair and Department of Cardiology, Medical University of Warsaw, Poland 2Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Center of Postgraduate Education Medical, European Health Center Otwock, Poland Abstract Prostacyclin and analogues are successfully used in the treatment of pulmonary arterial hypertension (PAH) due to their vasodilatory effect on pulmonary arteries. Besides vasodilatory effect, prostacyclin analogues inhibit platelets, but their antiplatelet effect is not thoroughly established. The antiplatelet effect of prostacyclin analogues may be beneficial in case of increased risk of thromboembolic events, or undesirable in case of increased risk of bleeding. Since prostacyclin and analogues differ regarding their potency and form of administration, they might also inhibit platelets to a different extent. This review summarizes the recent evidence on the antiplatelet effects of prostacyclin and analogue in the treatment of PAH, this is important to consider when choosing the optimal treatment regimen in tailoring to an individual patients’ needs. (Cardiol J 20XX; XX, X: xx–xx) Key words: prostacyclin analogues, pulmonary arterial hypertension, platelets, antiplatelet effect, thrombosis, bleeding Introduction tiproliferative effects [4]. The main indication for PGI2 and analogues is advanced pulmonary arterial Since 1935 when prostaglandin was isolated hypertension (PAH) and peripheral vascular disor- for the first time [1], many scientists have focused ders [5]. Treprostinil, iloprost and beraprost are the on a thorough study of arachidonic acid transforma- most frequently used prostacyclin analogues [4]. tion products and their various biological functions. Selexipag is a non-prostanoid IP receptor agonist One of the major prostaglandins is prostacyclin and a promising new alternative for classic PGI2 (PGI2), which was discovered by John R. Vane in analogues [6]. 1976 [2]. Endogenous PGI2 binds to prostacyclin As PGI2 analogues vary depending on the receptor (IP) on pulmonary vessels smooth muscle way of administration, pharmacokinetics, binding cells and platelets. Activated IP receptor induces and affinity for IP receptors, they may also inhibit production of cyclic adenosine monophosphate platelets to a different extent [5]. These differences (cAMP), which activates protein kinase A (PKA) result in various side effects and complications and results in smooth muscle relaxation, inhibi- associated with the of PGI2 analogues and impli- tion of platelet aggregation and reduction of cell cate the need to tailor the treatment according to proliferation [3]. Synthetic PGI2 analogues have a patient’s individual needs. Because the inten- a similar effect on cells as does natural PGI2. sity of antiplatelet effect of PGI2 analogues have Nowadays, PGI2 and its analogues are being used not been clarified, choosing the best therapeutic due to their vasodilating, antithrombotic and an- option for individual patients at high risk, or with Address for correspondence: Dr. Aleksandra Gąsecka, 1st Chair and Department of Cardiology, Medical University of Warsaw, ul. Banacha 1a, 02-097 Warszawa, Poland, tel: +48 518 343 599, e-mail: [email protected] Received: 1.07.2020 Accepted: 12.10.2020 *Sylwester P. Rogula and Hubert M. Mutwil share the first authorship. This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. www.cardiologyjournal.org 1 Cardiology Journal 20XX, Vol. XX, No. X Table 1. Receptors for prostacycline and its analogues on platelets. Receptor G-protein coupled Effect of activation Agonist DP [25, 49] Gs cAMP≠ epoprostenol, iloprost, treprostinil IP [23, 24, 25, 48] Gs > Gq cAMP≠ epoprostenol, iloprost, treprostinil, beraprost, selexipag TP [22] Gq > Gs = Gi cAMPØØ iloprost EP3 [23, 24] Gi > Gq = Gs cAMPØ epoprostenol, iloprost, beraprost cAMP — cyclic adenosine monophosphate a history of thrombosis or bleeding remains chal- activated by contact with the damaged vascular sur- lenging. This review (i) describes the role of PGI2 face, high molecular weight kininogen and kallikrein. in hemostasis, (ii) summarizes the recent evidence This complex initiates the cascade of activation of on the antiplatelet effect of PGI2 analogues in the factor XI and IX. The next step is the activation of treatment of PAH, and (iii) provides recommen- factor X, which starts the common pathway. Finally, 2+ dations regarding the choice of the optimal PGI2 factors Xa, Va and Ca form a complex that converts analogue in case of thrombosis or bleeding. prothrombin to thrombin, which then converts fibrinogen to fibrin to form a fibrin polymer. After Role of prostacyclin in hemostasis that, plasma transglutaminase (factor XIII) stabilises the clot. Although PGI2 is not directly involved in PGI2 plays a prominent role in hemostasis, clot formation, appropriate platelet aggregation is both due to its effect on vascular endothelium, a prerequisite for clotting. Hence, PGI2 may affect smooth muscle cells and platelets. When a blood secondary hemostasis and clot formation as well. vessel wall is damaged, collagen and von Wille- brand factor (vWF) are exposed enabling platelets Prostacyclin receptors adherence to the subendothelium and granule content release [7]. Thromboxane A2 (TxA2) and Prostacyclin receptors (IP) are seven-trans- adenosine diphosphate (ADP) released from, or membrane G protein-coupled receptors, exposed produced by activated platelets contribute to plate- on vascular smooth muscle cells and platelets [11]. let aggregation, which temporarily repairs vascular The main characteristics of the IP receptors are sum- injury. ADP also induces the conformation change marized in Table 1. There are four types of IP recep- of glycoprotein (GP) IIb/IIIa type receptor, allowing tors on platelets: IP, DP, TP, and EP3. The IP and DP binding of fibrinogen to GP IIb/IIIa and cross-link- receptors have anti-aggregatory effects, whereas the ing of the adjacent platelets. The released calcium TP, EP3 have pro-aggregatory effects [12]. ions (Ca2+) bind to phospholipids that are exposed Figure 1 shows the function of IP and DP re- on the surface of activated platelets and provide ceptors. The IP receptor works in two ways. First, a co-factor for the assembly of coagulation factors, it activates Gs protein, associated with adenylyl facilitating thrombus formation [8]. The processes cyclase (AC) to produce cAMP [13], resulting of primary hemostasis are counteracted by PGI2, in phosphorylation of the vasodilator-stimulated which is a thromboxane receptor antagonist. The phosphoprotein (VASP) by protein kinase A. VASP main task of PGI2 is to limit the coagulation to suppresses the activation of the membrane GP IIb/ the small area where it is needed, and to sustain /IIIa, thus preventing platelet aggregation [14]. patency of the blood vessel [9]. Second, IP activates Gq protein [15]. Activation of Following platelet-rich thrombus formation, Gq protein stimulates phospholipase C to synthe- further steps include activation of plasma coagula- size second messengers which increases the intra- tion factors and formation of crosslinked fibrin by cellular Ca2+ concentration. Increases Ca2+ reduces two pathways: extrinsic and intrinsic. The extrinsic the amount of cAMP, which might facilitate platelet pathway is activated by the tissue factor (TF) ex- aggregation [16]. However, the Gq-mediated effect posed by vessel injury and released from platelets, of PGI2 is less significant, so that the net effect of which is necessary for activation of factor VII. The PGI2 binding to IP receptor is anti-aggregatory. The complex consisting of Ca2+, TF and factor VII can DP receptor activates Gs protein only, therefore then activate factor X, which starts the common raising the intracellular cAMP concentration and pathway [10]. In the intrinsic pathway, factor XII is potentiating platelet inhibition. 2 www.cardiologyjournal.org Sylwester P. Rogula et al., Antiplatelet effects of prostacyclin analogues Due to the fact that the IP receptors have both PG12 anti- and pro-aggregatory modes of action, the net clinical effect (thrombosis and bleeding) of PGI2 and PG12 PG12 analogues are difficult to predict. Recently, there PG12 has been a search for a substance, which would specifically bind to the IP receptor, resulting in the introduction of selexipag [21]. Selexipag has a much Adenylate cyclase ADP higher affinity to platelet-inhibiting receptors (IP Adenylate cAMP cyclase and DP), and none to platelet-activating receptors Adenylate cyclase Kinase (TP and EP3). However, whether this specificity is A associated with a higher bleeding tendency remains to be investigated. Reduced Vasodilatation Antithrombotic vascular effect remodeling Differences in pharmacodynamics and pharmacokinetics of prostacyclin and analogues PGI2 and analogues are available in paren- teral and oral form. Different